Journal article
A Mechanism for the Synergistic Antimalarial Action of Atovaquone and Proguanil
Antimicrobial agents and chemotherapy, v 43(6), pp 1334-1339
Jun 1999
PMID: 10348748
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
A combination of atovaquone and proguanil has been found to be quite effective in treating malaria, with little evidence of the emergence of resistance when atovaquone was used as a single agent. We have examined possible mechanisms for the synergy between these two drugs. While proguanil by itself had no effect on electron transport or mitochondrial membrane potential (ΔΨ
m
), it significantly enhanced the ability of atovaquone to collapse ΔΨ
m
when used in combination. This enhancement was observed at pharmacologically achievable doses. Proguanil acted as a biguanide rather than as its metabolite cycloguanil (a parasite dihydrofolate reductase [DHFR] inhibitor) to enhance the atovaquone effect; another DHFR inhibitor, pyrimethamine, also had no enhancing effect. Proguanil-mediated enhancement was specific for atovaquone, since the effects of other mitochondrial electron transport inhibitors, such as myxothiazole and antimycin, were not altered by inclusion of proguanil. Surprisingly, proguanil did not enhance the ability of atovaquone to inhibit mitochondrial electron transport in malaria parasites. These results suggest that proguanil in its prodrug form acts in synergy with atovaquone by lowering the effective concentration at which atovaquone collapses ΔΨ
m
in malaria parasites. This could explain the paradoxical success of the atovaquone-proguanil combination even in regions where proguanil alone is ineffective due to resistance. The results also suggest that the atovaquone-proguanil combination may act as a site-specific uncoupler of parasite mitochondria in a selective manner.
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Details
- Title
- A Mechanism for the Synergistic Antimalarial Action of Atovaquone and Proguanil
- Creators
- Indresh K Srivastava - Department of Microbiology and Immunology, MCP Hahnemann School of Medicine, Philadelphia, PennsylvaniaAkhil B Vaidya - Department of Microbiology and Immunology, MCP Hahnemann School of Medicine, Philadelphia, Pennsylvania
- Publication Details
- Antimicrobial agents and chemotherapy, v 43(6), pp 1334-1339
- Publisher
- American Society for Microbiology
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000080601500004
- Scopus ID
- 2-s2.0-0033063070
- Other Identifier
- 991014878014904721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Microbiology
- Pharmacology & Pharmacy